tofacitinib and Dermatitis--Allergic-Contact

Topics: Asteraceae; Dermatitis, Allergic Contact; Humans; Patch Tests; Piperidines; Pyrimidines

The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow-derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.

Topics: Administration, Oral; Administration, Topical; Animals; Anti-Inflammatory Agents; Antipruritics; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Female; Inflammation; Janus Kinases; Lymph Nodes; Mice; Mice, Inbred BALB C; Piperidines; Pruritus; Pyrimidines; Pyrroles; Skin; Sulfonamides

The effect of CP-690550 (tofacitinib), a new Janus kinase (JAK) inhibitor, was evaluated in chronic allergic dermatitis. Allergic contact dermatitis was induced in rat ears by repeated application of oxazolone. This dermatitis was accompanied by sustained ear swelling and marked epidermal hyperplasia. In the induced ear, a lot of inflammatory cells infiltrated into the dermis site and the amounts of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-22 were elevated. Orally administered CP-690550 significantly suppressed ear swelling as well as epidermal thickening, and the effect at 10 mg/kg was comparable to that of cyclosporin A and etanercept. These results suggest a great potential of CP-690550, a JAK inhibitor, as a treatment for chronic dermatitis featuring epidermal hyperplasia (in the pathogenesis of which IFN-γ, TNF-α and IL-22 play a role) such as psoriasis and chronic atopic dermatitis.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Dermatitis, Allergic Contact; Ear; Female; Hyperplasia; Janus Kinases; Oxazolone; Piperidines; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Skin